In recent years, patients suffering from dyslipidemia (hyperlipidemia) and arteriosclerotic diseases induced thereby have been rapidly increased due to changes in dietary habits to take high calorie and high cholesterol-type foods with improvement of a living standard, obesity, lack of exercise, aging, and the like. It has been revealed from many etiological researches including the Framingham study that a low-density lipoprotein (LDL) cholesterol level positively correlates to an onset rate of heart diseases. Therefore, in drug therapies for dyslipidemia and arteriosclerosis, reduction of a LDL cholesterol value has been importantly focused (Non-patent document 1).
For hyper-LDL cholesterolemia, which is one of potent risk factors of cardiovascular diseases, therapeutic methods have been markedly progressed by the launch of HMG-CoA reductase inhibitors (statins). However, although statins potently reduce LDL cholesterol, decrease in cardiac accidents and mortality of cardiovascular diseases remains as high as about 30%. It is considered that a lower death risk of cardiovascular diseases can be achieved by further reducing LDL cholesterol. However, a high dose administration of statins cannot be applied due to enhanced increased risk of rhabdomyolysis.
Therefore, a medicament has been desired which has a potent reducing action on blood LDL cholesterol and is based on different mode of action from that of statins.
Proprotein convertases (PCs) are members of the mammalian serine protease family, of which homology to subtilisin in bacteria and kexin in yeast has been observed. One of PCs, PCSK9 (proprotein convertase subtilisin/kexin 9), is mainly expressed in the liver and secreted extracellularly, and then bound with LDL receptor on the membrane surfaces of hepatocytes to promote migration of the LDL receptor into the cells. The LDL receptor migrated into the cells are decomposed by cell organelles. Since the LDL receptor has a function of transporting lipoproteins containing LDL cholesterol to the liver from circulating blood, production of the PCSK9 protein inhibits uptake of blood LDL cholesterol into the liver, which results in an increase of blood LDL cholesterol level. In fact, it is known that LDL blood cholesterol level is high in humans with a function acquisition-type mutation in the PCSK9 gene, which relates to autosomal dominant hypercholesterolemia (Non-patent document 2). Whilst, a low level of blood LDL cholesterol is maintained in humans with a function deletion type mutation in the PCSK9 gene (Non-patent document 3). Further, it has been demonstrated in an animal that LDL cholesterol level is low in mice deficient in the PCSK9 gene of the liver (Non-patent document 4).
It is considered from the reasons set forth above that reduction of the amount of the PCSK9 protein by suppression of the production thereof or inhibition against the function of the PCSK9 protein leads to increase in the amount of the LDL receptor, and thus provides a potent LDL cholesterol-reducing action.
Under the circumstances, active researches have recently been conducted on functional inhibition of the PCSK9 protein or suppression of the production thereof. For example, as those using an antibody or antisense oligonucleotide, functional inhibition of the PCSK9 protein using a monoclonal antibody directed to PCSK9, suppression of the PCSK9 protein production based on RNA interference, and the like have been reported (Non-patent documents 5 to 7). Further, as those using a low molecular weight compound, it has been reported that berberine reduces mRNA and protein level of PCSK9 in HepG2 cells (Non-patent document 8), and 5-azacytidine, which is an annexin A2 activator, promotes binding of the PCSK9 protein with annexin A2 and suppresses decomposition of LDL receptor (Patent document 1). However, almost no compounds with a low molecular weigh as inhibitors against PCSK9 protein function or suppressors against PCSK9 protein production have been reported except for those mentioned above.
Patent document 2 discloses pyrimidine compounds having a dibenzylamine structure, which have potent inhibitory activity against cholesteryl ester transfer protein (CETP), and also have a potent blood HDL cholesterol-increasing action. The document discloses the compound of the following formula (I) as a racemate in Example 45:
(trans-{4-[({2-[({1-[3,5-bis(trifluoromethyl)phenyl]ethyl}{5-[2-(methylsulfonyl)ethoxy]pyrimidin-2-yl}amino)methyl]-4-(trifluoromethyl)phenyl}(ethyl)amino)methyl]cyclohexyl}acetic acid, henceforth also referred to as “racemate compound (I)” in the specification). However, any relationship between the racemate compound (I) and the PCSK9 protein has not been described or suggested.
Since PCs have influences on proliferation, motility, adhesion, and invasion of cancer cells, they have been focused as a target of cancer treatment (Non-patent document 9). There are also known relationship of PCs with obesity, diabetes, and Alzheimer disease, and involvements of PCs in diseases such as viral infectious diseases including acquired immunodeficiency syndrome (AIDS) and severe acute respiratory syndrome (SARS) (Non-patent documents 10 and 11).
Therefore, use of a compound having a reducing action on amount of PCSK9 protein or an inhibitory action against PCSK9 protein function as an active ingredient of a medicament for the aforementioned diseases is also expected.